Project Summary/Abstract: Unlike many organs that undergo age-related degeneration, the prostate gland undergoes age- related enlargement leading to significant health complications in the majority of men over 60 years old. Increasing evidence indicates a central role for prostate stem/progenitor cells and abnormal activation of prostate regeneration pathways leading to prostate enlargement. Current treatment approaches for prostatic enlargement primarily revolve around therapies targeting the androgen receptor (AR), which can partially alleviate symptoms but do not achieve permanent disease remission. Our laboratory recently determined that the important stem cell factor SOX2 is an important stem/progenitor and survival factor during prostate development and regeneration. SOX2 is a transcription factor that is essential for maintaining survival and pluripotency of embryonic and many adult stem cells, and canonically interacts with OCT4 to promote stem cell gene expression and repress differentiation. This proposal builds upon our work demonstrating an important and novel non-stem cell and prostate-specific function for SOX2 in the prostate, whereby SOX2 promotes resistance to AR-targeted therapies and expansion of stem/progenitor cells to promote prostate enlargement. However, there remain significant gaps in our understanding of the mechanistic role of SOX2 in prostate enlargement; filling such knowledge gaps has a high potential to functionally implicate SOX2 and SOX2-target genes as new therapeutic targets to prevent and treat age-related prostate enlargement. The long-term goal of this project is to identify signaling pathways regulated by SOX2 in prostate epithelial cells that can be targeted to prevent and therapeutically treat prostate enlargement. The objective is to define how SOX2 promotes the survival of multipotent prostate epithelial cells and contributes to prostate stem cell expansion glandular enlargement and begin testing novel strategies to deplete prostate progenitor cell populations. Our central hypothesis is that the quantity of SOX2-positive prostate cells increases during aging, and SOX2 enables resistance to AR-targeted therapies, thereby promoting prostate enlargement.